title: Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.
abstract: Ovarian cancer, which is the leading cause of death from gynecological malignancies, is a heterogeneous disease known to be associated with disruption of multiple signaling pathways. Nevertheless, little is known regarding the role of protein phosphatases in the signaling events that underlie the disease; such knowledge will be essential to gain a complete understanding of the etiology of the disease and how to treat it. We have demonstrated that protein-tyrosine phosphatase 1B (PTP1B) was underexpressed in a panel of ovarian carcinoma-derived cell lines, compared with immortalized human ovarian surface epithelial cell lines. Stable restoration of PTP1B in those cancer cell lines substantially decreased cell migration and invasion, as well as proliferation and anchorage-independent survival. Mechanistically, the pro-survival IGF-1R signaling pathway was attenuated upon ectopic expression of PTP1B. This was due to dephosphorylation by PTP1B of IGF-1R β-subunit and BRK/PTK6, an SRC-like protein-tyrosine kinase that physically and functionally interacts with the IGF-1R β-subunit. Restoration of PTP1B expression led to enhanced activation of BAD, one of the major pro-death members of the BCL-2 family, which triggered cell death through apoptosis. Conversely, inhibition of PTP1B with a small molecular inhibitor, MSI-1436, increased proliferation and migration of immortalized HOSE cell lines. These data reveal an important role for PTP1B as a negative regulator of BRK and IGF-1Rβ signaling in ovarian cancer cells.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Fan
authors.forename: Guang
authors.initials: G
authors.lastname: Lin
authors.forename: Robert
authors.initials: R
authors.lastname: Lucito
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Tonks
mesh_terms: D045744:Cell Line, Tumor; D002776:Cholestanes / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010766:Phosphorylation / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; C494819:BAD protein, human; D002776:Cholestanes; D009363:Neoplasm Proteins; D051025:bcl-Associated Death Protein; D013096:Spermine; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C088375:PTK6 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: BRK; Cell Death; Dephosphorylation; IGF-1R; Ovarian Cancer; PTP1B; Phosphorylation; Tyrosine-protein Kinase (Tyrosine Kinase); Tyrosine-protein Phosphatase (Tyrosine Phosphatase)